The development of effective therapy for children with acute lymphoblastic leukemia (ALL) is one of the great successes of clinical oncology, with long-term survival achieved by over 80% of patients. However, therapy remains non-specific, toxic and sometimes lethal. Moreover, cure rates for adults with ALL remain relatively, low, with only 40% of patients cured. The goal of Project 6 is to maximize the therapeutic index (the efficacy:toxicity balance) in the treatment of ALL. We seek to increase cure rates, decrease acute and long-term morbidity, identify novel prognostic factors and perform clinical trials with new agents discovered within this Program Project. In Specific aim 1, we extend our successful clinical pediatric program to include adult patients (age 18-50 years), affording us the unique opportunity to directly compare uniformly treated adults and children in terms of response to therapy, toxicity and underlying biology. Specific aim 2 will seek to optimize dosing of asparaginase, a chemotherapeutic agent utilized in all regimens for adult and pediatric ALL, by determining the relative efficacy, toxicity and pharmacodynamics of intravenous polyethylene glycosylated (PEG) asparaginase and intramuscular native E.coli asparaginase. Specific aim 3 will explore the pathogenesis and pharmacogenomic predictors of doxorubicin cardiotoxicity by studying the association between cardiac outcome and mutations of mitochondrial DMA and/or hemochromatosis genes, and also continue our long-term assessment of doxorubicin cardiotoxicity, including the value of serial monitoring during treatment and the effects of continuous infusions of doxorubicin and dexrazoxane in preventing cardiomyopathy. We are committed to rapid translation of discoveries from Projects 1-5 and have already put that goal into action by conducting a Phase l/ll trial of gamma secretase inhibitors in children and adults with relapsed T-cell ALL. In Specific aim 4, we will continue to initiate innovative clinical trials of targeted therapies based on the findings from our laboratories, including not just the gamma secretase inhibitor trial, but also studies of the mTOR inhibitor, rapamycin, to enhance steroid-induced apoptosis, and novel kinase inhibitors, with the plan to incorporate active agents into upfront therapy for high risk patients aged 1-50 years.